Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice

Abstract

The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived). Elevated extracellular Ca2+concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR mediated, as, in both cell types, overexpression of a dominant-negative CaR attenuated high Ca2+-stimulated chemotaxis. We also demonstrated expression of a β-chemokine, monocyte chemoattractant protein-1 (MCP-1), and its receptor, CC motif receptor-2 (CCR2), in the hypothalamic GnRH neurons as well as in GT1-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines in a dose-dependent fashion; the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high Ca2+promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, in the preoptic area of anterior hypothalamus, the number of GnRH neurons was ∼27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1.

Lipopolysaccharide-Induced Maternal Inflammation Affects the Gonadotropin-Releasing Hormone Neuron Development in Fetal Mice

“…There is evidence to suggest that maternal inflammation dramatically disturbs the cytokine balance in fetuses, producing a long-term programming effect on neuronal development [19,25,26]. In recent years, data have been accumulated on the involvement of cytokines in the development of olfactory structures and migration of GnRH neurons [14,16]. We demonstrated that LPS treatment can significantly increase the levels of maternal serum proinflammatory cytokines within 1.5 h and the effect was still evident at 3 h for IL-6, MCP-1, LIF and TNF-α (fig.…”

“…Using GN11 cells as a model of immature, migratory GnRH neurons, Magni et al [16] showed that LIF induced their chemokinesis. MCP-1 and its receptor, chemokine (C-C motif) receptor-2 (CCR2), were found to be expressed in the hypothalamic GnRH neurons as well as in the GT1-7 and GN11 cell lines, with MCP-1 stimulating migration of these immature GnRH neurons [14]. …”

“…Cytokines such as leukemia inhibitory factor (LIF), monocyte chemotactic protein (MCP)-1 and hepatocyte growth factor interact in the organization of GnRH neuron migration in the nasal compartment. Expression of these cytokines and their receptors were detected in the nasal compartment of mouse fetuses on E 13.5 [14,15,16]. …”

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

“…(21). In gonadotropin-releasing hormone neurons the activation of these Ca 2þ receptors promotes cell migration (35).…”

Ca2+ chemotaxis inDictyostelium discoideum

“…The soluble Ca 2+ concentration is approximately 1.1-1.3 mM in the extracellular fluids of tissues (Breitweiser, 2008) and 2.5 mM in blood (Bronner, 1997). Evidence suggests that free extracellular Ca 2+ might play a role as a chemoattractant in addition to cell-type-specific chemoattractants in a variety of developmental processes, including embryonic development (Adams et al, 2006;Chattopadhyay et al, 2007;Reitz et al, 1977), wound healing (Menon et al, 1985;Morris and Chan, 2007), angiogenesis (Aguirre et al, 2010), the immune response (Olszak et al, 2000) and tissue maintenance (Quarles et al, 1997). For example, mammalian gonadotropin-releasing hormone (GnRH) neurons undergo chemotaxis in Ca 2+ gradients generated in vitro, which has led to the hypothesis that Ca 2+ gradients in combination with gradients of the monocyte chemoattractant protein (MCP-1) regulate GnRH neuron migration during development Bandyopadhyay et al, 2007).…”